Alternative titles; symbols
HGNC Approved Gene Symbol: PHB1
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:49,404,052-49,414,882 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.33 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 |
Prohibitin is a 30-kD intracellular, antiproliferative protein (White et al., 1991).
White et al. (1991) mapped the PHB gene to chromosome 17 by analysis of human-mouse somatic cell hybrid cell lines using a genomic fragment of human prohibitin DNA isolated from a library using the rat prohibitin cDNA clone. By a study of cell lines containing portions of human chromosome 17, they determined that the PHB gene was located in the 17q11.2-q23 region. By in situ hybridization, they localized the gene to 17q21. Sato et al. (1992) isolated the human homolog of the rat prohibitin gene and mapped it to 17q12-q21 by in situ hybridization.
Sato et al. (1993) showed that the human prohibitin gene family consists of 1 functional PHB gene on 17q21 and 4 processed pseudogenes, each on a different chromosome: PHBP1 on 6q25, PHBP2 on 11p11.2, PHBP3 on 1p31.3, and PHBP4 on 2q21.
Proliferation of tumor cells depends on new blood vessel formation (angiogenesis) that accompanies malignant progression. Anticancer therapies using angiogenesis inhibitors or cytotoxic agents targeted to the vasculature of tumors have been evaluated in clinical trials. Although white fat is a nonmalignant tissue, it has the capability to quickly proliferate and expand. Furthermore, it is highly vascularized. Rupnick et al. (2002) showed that nonspecific angiogenesis inhibitors can prevent the development of obesity of mice. Kolonin et al. (2004) used in vivo phage display to isolate a peptide motif (amino sequence CKGGRAKDC) that homes to white fat vasculature. They showed that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and thus established prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat in mice. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, the work suggested the development of targeted drugs for treatment of obese patients.
Prohibitins form a ring-like, high-molecular-mass complex at the inner membrane of mitochondria. Artal-Sanz and Tavernarakis (2009) demonstrated that the mitochondrial prohibitin complex promotes longevity by modulating mitochondrial function and fat metabolism in C. elegans. They found that prohibitin deficiency shortened the life span of otherwise wildtype animals. Knockdown of prohibitin promoted longevity in diapause mutants or under conditions of dietary restriction. In addition, prohibitin deficiency extended the life span of animals with compromised mitochondrial functions or fat metabolism. Depletion of prohibitin influenced ATP levels, animal fat content, and mitochondrial proliferation in a genetic-background- and age-specific manner. Artal-Sanz and Tavernarakis (2009) concluded that their findings revealed a novel mechanism regulating mitochondrial biogenesis and function, with opposing effects on energy metabolism, fat utilization, and aging in C. elegans.
By gel filtration, mass spectrometry, coimmunoprecipitation, and Western blot analysis of HeLa cells, Da Cruz et al. (2008) showed that prohibitin-1 and prohibitin-2 (PHB2; 610704) interacted in a 250-kD complex with SLP2 (STOML2; 608292). Knockdown of SLP2 in HeLa cells or mouse embryonic fibroblasts via RNA interference led to increased proteolysis of the prohibitins and other mitochondrial proteins.
Using coimmunoprecipitation analysis, Christie et al. (2011) confirmed that SLP2 interacted with PHB1 and PHB2. Elevated SLP2 content increased the association of PHB1 with mitochondrial membranes.
By DNA sequence analysis of 2 exons in the PHB gene in 23 sporadic breast cancers that showed loss of heterozygosity on 17q or developed in patients 35 years old or younger, Sato et al. (1993) identified 4 cases of somatic mutation: 2 of these were missense mutations, 1 showed a 2-bp deletion resulting in truncation of the gene product due to frameshift, and the fourth was a splice site mutation. Sato et al. (1993) found no mutations in the PHB gene in other forms of tumors, namely, those of ovary, liver, and lung.
In breast cancer cell lines, Jupe et al. (1996) identified a point mutation at position 729 in the prohibitin 3-prime untranslated region (base 1630 in the full-length transcript). The change was identified as a single-nucleotide polymorphism (SNP), +729C-T (176705.0001), in which the variant T allele lacked the antiproliferative activity of the more common functional C allele. The observation led to the hypothesis that women carrying the prohibitin T allele have increased susceptibility to breast cancer. Jupe et al. (2001) found an association between the T allele and breast cancer in women who reported a first-degree relative with the disease, and an even stronger association in a subset of women diagnosed at or before age 50 years. They suggested that prohibitin genotyping has value in assessing risk of breast cancer in women aged 50 years or younger with at least 1 first-degree relative with the disease.
In breast cancer cell lines, Jupe et al. (1996) identified a point mutation at position +729 in the prohibitin 3-prime untranslated region (base 1630 in the full-length transcript). The change was identified as a +729C-T transition in which the variant T allele lacked the antiproliferative activity of the more common functional C allele. The observation led to the hypothesis that women carrying the prohibitin T allele have increased susceptibility to breast cancer.
Jupe et al. (2001) performed a case-control study of prohibitin genotype in 205 women with breast cancer and 1,046 healthy controls. The results showed an association between the T allele and breast cancer in women who reported a first-degree relative with the disease (odds ratio 2.5, p = 0.005). An even stronger association was found in a subset of women diagnosed at or before age 50 years (4.8, p = 0.003). Jupe et al. (2001) suggested that prohibitin genotyping has value in assessing risk of breast cancer in women aged 50 years or younger with at least 1 first-degree relative with the disease.
Artal-Sanz, M., Tavernarakis, N. Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 461: 793-797, 2009. [PubMed: 19812672] [Full Text: https://doi.org/10.1038/nature08466]
Christie, D. A., Lemke, C. D., Elias, I. M., Chau, L. A., Kirchhof, M. G., Li, B., Ball, E. H., Dunn, S. D., Hatch, G. M., Madrenas, J. Stomatin-like protein 2 binds cardiolipin and regulates mitochondrial biogenesis and function. Molec. Cell. Biol. 31: 3845-3856, 2011. [PubMed: 21746876] [Full Text: https://doi.org/10.1128/MCB.05393-11]
Da Cruz, S., Parone, P. A., Gonzalo, P., Bienvenut, W. V., Tondera, D., Jourdain, A., Quadroni, M., Martinou, J.-C. SLP-2 interacts with prohibitins in the mitochondrial inner membrane and contributes to their stability. Biochim. Biophys. Acta 1783: 904-911, 2008. [PubMed: 18339324] [Full Text: https://doi.org/10.1016/j.bbamcr.2008.02.006]
Jupe, E. R., Badgett, A. A., Neas, B. R., Craft, M. A., Mitchell, D. S., Resta, R., Mulvihill, J. J., Aston, C. E., Thompson, L. F. Single nucleotide polymorphism in prohibitin 3-prime untranslated region and breast-cancer susceptibility. Lancet 357: 1588-1589, 2001. [PubMed: 11377649] [Full Text: https://doi.org/10.1016/s0140-6736(00)04747-4]
Jupe, E. R., Liu, X. T., Kiehlbauch, J. L., McClung, J. K., Dell'Orco, R. T. Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 3-prime untranslated region mutations. Cell Growth Diff. 7: 871-878, 1996. [PubMed: 8809404]
Kolonin, M. G., Saha, P. K., Chan, L., Pasqualini, R., Arap, W. Reversal of obesity by targeted ablation of adipose tissue. Nature Med. 10: 625-632, 2004. [PubMed: 15133506] [Full Text: https://doi.org/10.1038/nm1048]
Rupnick, M. A., Panigrahy, D., Zhang, C.-Y., Dallabrida, S. M., Lowell, B. B., Langer, R., Folkman, M. J. Adipose tissue mass can be regulated through the vasculature. Proc. Nat. Acad. Sci. 99: 10730-10735, 2002. [PubMed: 12149466] [Full Text: https://doi.org/10.1073/pnas.162349799]
Sato, T., Saito, H., Swensen, J., Olifant, A., Wood, C., Danner, D., Sakamoto, T., Takita, K., Kasumi, F., Miki, Y., Skolnick, M., Nakamura, Y. The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer. Cancer Res. 52: 1643-1646, 1992. [PubMed: 1540973]
Sato, T., Sakamoto, T., Takita, K.-I., Saito, H., Okui, K., Nakamura, Y. The human prohibitin (PHB) gene family and its somatic mutations in human tumors. Genomics 17: 762-764, 1993. [PubMed: 8244394] [Full Text: https://doi.org/10.1006/geno.1993.1402]
White, J. J., Ledbetter, D. H., Eddy, R. L., Jr., Shows, T. B., Stewart, D. A., Nuell, M. J., Friedman, V., Wood, C. M., Owens, G. A., McClung, J. K., Danner, D. B., Morton, C. C. Assignment of the human prohibitin gene (PHB) to chromosome 17 and identification of a DNA polymorphism. Genomics 11: 228-230, 1991. Note: Erratum: Genomics 11: 732 only, 1991. [PubMed: 1684951] [Full Text: https://doi.org/10.1016/0888-7543(91)90126-y]